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CONTEXT: Practitioners often combine 2 or more second-generation antipsychotics (SGAs) in patients with bipolar disorder, despite an absence of data to support their safety, tolerability, or efficacy. OBJECTIVE: This study sought to evaluate the safety and tolerability of SGA polytherapy compared to SGA monotherapy in bipolar disorder patients receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). METHOD: A longitudinal cohort of 1,958 patients who were prescribed at least 1 SGA was drawn from 4,035 bipolar patients in STEP-BD recruited between November 1999 and July 2005 and assessed at least quarterly for a mean duration of 21 months. Main outcome measures were the mean quarterly prevalence of adverse events, medical and psychiatric service usage, Global Assessment of Functioning ratings, and percentage of days spent well. RESULTS: Almost 10% of patients taking SGAs were prescribed SGA polytherapy. After controlling for illness onset, age, baseline illness severity, and medication load, patients prescribed SGA polytherapy, compared to monotherapy, exhibited more dry mouth (number needed to harm [NNH] = 4), tremor (NNH = 6), sedation (NNH = 8), sexual dysfunction (NNH = 8), and constipation (NNH = 11) and were almost 3 times as likely to incur more psychiatric and medical care; there was no association with greater global functioning scores or percentage of days spent well. CONCLUSIONS: Although SGA polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and health service use but not with improved clinical status or function. Thus, SGA polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.

Original publication




Journal article


J Clin Psychiatry

Publication Date





240 - 247


Adult, Antipsychotic Agents, Bipolar Disorder, Cohort Studies, Drug Therapy, Combination, Drug-Related Side Effects and Adverse Reactions, Female, Health Services, Humans, Longitudinal Studies, Male, Middle Aged, Psychiatric Status Rating Scales, Treatment Outcome, United States, Utilization Review